Pure enantiomers are used in the synthesis of, inter alia, pharmaceuticals, agrochemicals, flavours and fragrances. Asymmetric chemocatalysis is an efficient production method for chiral molecules. Current large-scale protocols, however, rely on the use of organic solvents, making these methods expensive and problematic from a safety and environmental impact point of view.
Chiral noble-metal complexes in aqueous solutions are known in the art. Kan-To Wan et al. (Tetrahedron Asymmetry, Pergamon Press Ltd, Oxford, GB, pages 2461-2467, 1 Jan. 1993) shows a sulfonated ruthenium BINAP (Binaphtalendiyl-bis[diphenylphosphine) complex. WO2007104690 shows a ruthenium phosphine complex. U.S. Pat. No. 5,827,794 shows a sulfonated ruthenium BINAP complex.
Asymmetric synthesis employing metal catalysts with chiral ligands are described in U.S. Pat. No. 5,324,870, which shows the use of a chiral ruthenium phosphine complex in hydrogenation reactions, in Touati et al. (Tetrahedron Asymmetry, Pergamon Press Ltd, Oxford, GB, pages 3400-3405, 27 Dec. 2006), which shows asymmetric hydrogenation reactions catalysed by a ruthenium SYNPHOS complex, in Duprat et al. (Tetrahedron Letters, 44(4), pages 823-826, 2003), which shows a ruthenium SYNPHOS complex, and in WO9215400 which shows a ruthenium BINAP complex.
In summary, known methods for asymmetric catalysis use organic solvents. Water is a desirable solvent for conducting asymmetric syntheses with ruthenium catalysts, particularly in view of technical-scale applications.
Rhodium-catalyzed asymmetric hydrogenations of different substrates in aqueous/surfactant media and/or biphasic systems have been explored by Grassert et al. (J. Organomet. Chem., 621, pages 158-165, 2001) they show a 1,5-cyclooctadiene)bismethylallylrhodium phosphine complex.
The ligands used in aqueous solutions differ from conventional chiral ligands—which are insoluble in water—by the addition of chemical groups to render them water soluble. This modification is expensive.
The ability to use water-insoluble chiral ligands in aqueous phase catalysis would be of advantage. To the knowledge of the present inventors, however, chiral synthesis employing chiral water-insoluble ruthenium containing catalysts in aqueous media has not been accomplished so far.
Based on this background, it is the objective of the present invention to provide means and methods for chiral hydrogenation reactions in aqueous media.
Surprisingly it was found that under conditions of low pH, water-insoluble catalysts can be made and used in aqueous media, particularly in the absence of any organic solvent. It was further found that such catalyst can be activated in aqueous media.